New developments in HPV vaccines

Ian Frazer, Research Director, The Translational Research Institute Brisbane, Australia

Cervical cancer is 100% due to HPV infection, and kills 250,000 women per year, mostly in the developing

world

ALL CANCERS CERVICAL CANCER

Papillomavirus vaccine development

Cancer associated Human

Papillomaviruses(~1980)

Zur Hausen

Harriet Richardson, Gail Kelsall, Pierre Tellier, Helene Voyer, Michal Abrahamowicz, Alex Ferenczy, Francois Coutlee, and Eduardo L. Franco Cancer Epidemiology, Biomarkers & Prevention Vol. 12, 485–490, June 2003

HPV 16

First learn the natural history of the disease

Fract

ion infe

cted

Months since onset of Sexual activity- High risk HPV infection is common- Two common (16,18) and several rarer

types- >95% resolve spontaneously –median

1.5yrs- 2% progress to cancer over 15 years- Unexpectedly, detection of pre-cancer is

possible 1- 2 years post infectionR

esi

dual in

fect

ion

Vaccines to prevent HPV infection

Cancer associated Human

Papillomaviruses(~1980)

-Some HPVs cause cancer - Virus can’t be grown in the lab

Virus Like particles1

(~1990)

- L1 recombinant DNA

- Self assembly to VLPs

- VLPs highly immunogenic

1:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1):251-257, 1991.

Jian Zhou

Zur Hausen

HPV vaccine development:A 15 year $1 billion process

Cancer associated

Human Papillomaviruses

(~1980)

Virus Like particles1

(~1990)

HPV vaccines(~2005)

-Conventional vaccines- VLPs+ adjuvant

- Neutralising Antibody- Protection > 5yrs

-Cervarix – HPV 16, 18-Gardasil – HPV 6,11,16,181:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1):251-257, 1991.

Jian Zhou

Zur Hausen

Disclosure of conflict of interest

Dr Ian Frazer and the University of Queensland benefit financially from commercial sale of the prophylactic HPV vaccines discussed in this talk

-needing many people and a hard end point to prove efficacy

Study1 Vaccine2 No of subjects End-points

Vaccine efficacy1

Vaccine Control % ( confidence limits)

Koutsky 6/11/16/18 6087 6080 CIN 2/3 AIS 98 (86-100)

Ault 6/11/16/18 10291 10292 CIN 2/3 AIS 99 (93-100)

Garland 6/11/16/1822412261

22582279

CIN 2/3 AISGW VIN VAIN

100 (94-100)100 (94-100)

Joura 6/11/16/187811 7785 VIN2/3 VAIN

2/3100 (72-100)

Parvonen* 16/18 9319 9325 CIN2,3 93 (89-98)

Adapted from J. A. Kahn and R. D. Burk. Papillomavirus vaccines in perspective. Lancet 369 (9580):2135-2137, 2007.

*: Phase III bivalent vaccine data from 25th IPV Malmo 2009

1: prevention of premalignancy in HPV naïve subjects, for prevention of disease caused by vaccine HPV types

Since the introduction of vaccination in Australia,HPV related disease has virtually disappeared in

vaccinated young women

Ali, H. Et al BMJ 2013;346:f2032 doi: 10.1136/bmj.f2032

Nine steps to prevention of HPV associated cancer

• Define the problem – HPV and cancer Zur Hausen

• Develop the science –recombinant VLPS Jian Zhou• Find commercial partners

Merck/GSK• Scale up the manufacture

Merck/GSK• Complete safety and efficacy trials Many

groups• Educate the profession, govt, the public Ongoing• Confirm field efficacy • Improve the product

– 9 valent vaccines, 2 dose regimens• Encourage deployment globally• Develop effective immunotherapy

ENABLING GLOBAL USAGE

3

North America:

USACanada Mexico

9

South America:Brazil Bolivia+Argentina UruguayPeru EcuadorColombia ChileParaguay

38

Middle East & Africa:

Gabon NamibiaIsrael C.A.R.+Morocco MauritiusKenya+ KuwaitMauritania UAE Guinea Eq. Ethiopia+Uganda+ Togo+Malawi+ Congo Brazzaville Congo Kinsh (DRC)+Jordan Egypt Niger+Cote d’Ivoire+ Burkina Faso+ Ghana+Chad+ Bahrain BotswanaLebanon Tanzania+ Zambia+

South Africa Cameroon+ Nigeria+Tunisia Mali+ QatarGuinea Conakry+ Saudi Arabia Rwanda+

25

Asia Pacific & Japan:Kyrgyzstan+Uzbekistan+KazakhstanAustraliaIndonesia KoreaTaiwanHong KongSingaporeNew ZealandMacauMalaysiaPhilippinesThailandIndia+Vietnam+FijiBhutanJapanSri LankaBruneiAzerbaijanPakistan+TurkmenistanNepal

42

Europe:

Germany Cyprus Ireland France Czech Republic

LatviaUK Denmark LithuaniaSpain Estonia LuxembourgItaly Finland MaltaAustria Greece NetherlandsBelgium Hungary NorwayBulgaria Iceland PolandPortugal Romania SlovakiaSlovenia Sweden SerbiaMontenegro Switzerland LiechtensteinBosnia/Herzegovina+ RussiaBelarus Croatia Turkey UkraineMacedonia AlbaniaGeorgia

Caribbean & Central America:

Costa Rica Trinidad/TobagoPuerto Rico El SalvadorGuatemala HondurasCuracao Nicaragua+Bermuda PanamaBahamas Cayman IslandsBarbados ArubaJamaica Dominican Republic

16

HPV Vaccine Approval is world-wide

+GAVI – Eligible Registration Approvals (27 out of 56): Bolivia, Bosnia/Herzegovina, Burkina Faso, Cameroon, Central African Republic, Chad, Congo (DR), Cote d’Ivoire, Ethiopia, Ghana, Guinea (Conakry), India, Kenya, Kyrgyzstan, Malawi, Mali, Mauritania, Nicaragua, Niger, Nigeria, Pakistan, Rwanda, Tanzania, Togo, Uganda, Uzbekistan, Vietnam, Zambia, Nepal.

HPV vaccine use (in green) is in the developed world

Cervical cancer (in purple) is in the developing world

http://www.indexmundi.com/blog/wp-content/uploads/2013/05/HPV-vaccine-infographic.jpg

Study 1 -Screening

• Aim: Compare cervical cancer screening strategies in 30 + year old women

• P.I. : Dr Mgt McAdam• Methods:

– 500 women between 30 and 50 recruited

– VIA, VILI, Colposcopy, Cervical Cytology (Brisbane), HPV DNA (Digene)

– Referred for biopsy if any test positive.

1% of Vanuatu women will get cervical cancer! Vaccine delivery needs staffing, and a cold chain

Vanuatu->50 islands~250,000 people~25 doctors-91 parliamentarians!-1 vaccine fridge-0 reliable electricity

500 well women over 30

Bx result Number

Cancer 5

CIN 3 17

CIN 1 23

Education is the key to successful vaccine delivery: parents, children, staff, and government

Parents and Kids under the Banyan Tree- north Efate

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When vaccine is available, vaccination programs can be as

successful in Vanuatu as Australia

State Age Dose 1 Coverage (%)

Dose 1 immunised receiving

Dose 2 (%) Dose 3 (%)

Australia 12-18 (Opt out)

~ 90% 96 86

Australia 18-25 (Opt in) ~80% 82 50

Vanuatu 10-12 (Opt out)

~80% 98 93~80% coverage for bivalent HPV vaccine for 10-12 year olds in 2008, and 2013Vaccine through Australian Cervical Cancer Foundation: delivery by government

Port Vila

Port Vila Hospital

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